ESTRO 2025 - Abstract Book

S3878

Radiobiology - Immuno-radiobiology

ESTRO 2025

PDAC cell lines. Both radiation modalities induce similar immunogenic effects given the same physical dose. The immunogenic radiation response in human PDAC is temporally modulated and comprises pro- as well as anti immunogenic effects.

Keywords: pancreatic cancer, protons, cGAS/STING

2348

Digital Poster DNA damage response inhibitors enhance interferon signaling in an LET-dependent manner after irradiation of glioblastoma cells Gro Elise Rødland 1 , Mihaela Temelie 2 , Adrian Eek Mariampillai 1 , Ana Maria Serban 2 , Nina Frederike J. Edin 3 , Eirik Malinen 1 , Lilian Lindbergsengen 1 , Antoine Gilbert 4 , François Chevalier 4 , Diana I. Savu 2 , Randi G. Syljuåsen 1 1 Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. 2 Department of Life and Environmental Physics, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, Magurele, Romania. 3 Department of Physics, University of Oslo, Oslo, Norway. 4 UMR6252 CIMAP, Team Applications in Radiobiology with Accelerated Ions, CEA-CNRS-ENSICAEN-Université de Caen Normandie, Caen, France Purpose/Objective: Interferon (IFN) signaling plays an important role in antitumor immune responses. Inhibitors of the DNA damage response, such as ATR inhibitors, can increase IFN signaling upon conventional radiotherapy with X-rays. However, it is not known whether such inhibitors also enhance IFN signaling after irradiation with high linear energy transfer (LET) particles. Material/Methods: Human glioblastoma U-251 and T98G cells were irradiated with X-rays (LET: ~4 keV/mm; 2-30 Gy), protons (LET: 4.8 and 41.9 keV/mm; 2-6 Gy) and carbon ions (LET: 28 and 73 keV/mm; 1-4 Gy), with and without ATR inhibitor (VE-822 at 50-250nM) or ATM inhibitor (AZD1390 at 10nM). DNA damage signaling events and cell cycle distribution were analyzed by immunoblotting and flow cytometry. Radiosensitivity was assessed by clonogenic survival assay. IFN ß secretion was measured by ELISA, and IFN-dependent STAT1 activation was examined by immunoblotting. Results: High-LET protons and carbon ions caused stronger activation of the DNA damage response compared to low-LET protons and X-rays at similar radiation doses. This was evident from quantitative analysis of phospho-ATM S1981, phospho-CHK1 S317, phospho-CHK1 S345 and γH2AX signals at 0-4 hours post treatment, and by assessment of G2 checkpoint arrest at 24 hours. The G2 checkpoint arrest was abrogated by the ATR inhibitor and prolonged by the ATM inhibitor after all radiation types. The inhibitors also increased radiosensitivity, as measured after X- and carbon ion irradiation. The sensitizing effect of the ATM inhibitor was smaller with carbon ions than with X-rays, whereas the effect of the ATR inhibitor was about the same with the different radiation modalities. ATR inhibition increased IFN signaling following both low-LET and high-LET irradiation. ATM inhibition also increased IFN signaling, but to a lesser extent. Notably, both cell lines secreted significantly more IFN-ß when the inhibitors were combined with high-LET compared to low-LET irradiation. This was found when compared to both low and high doses of X rays. Conclusion: These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET. DNA damage response inhibitors may potentially be used in combination with proton or carbon ion therapy to enhance tumor cell radiosensitivity and boost antitumor immune responses.